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WO1996011901A1 - NOUVEAUX ACIDES α,α,α',α'-TETRACHLORODICARBOXYLIQUES, LEUR PROCEDE DE PREPARATION ET MEDICAMENTS LES CONTENANT - Google Patents

NOUVEAUX ACIDES α,α,α',α'-TETRACHLORODICARBOXYLIQUES, LEUR PROCEDE DE PREPARATION ET MEDICAMENTS LES CONTENANT Download PDF

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Publication number
WO1996011901A1
WO1996011901A1 PCT/EP1995/003980 EP9503980W WO9611901A1 WO 1996011901 A1 WO1996011901 A1 WO 1996011901A1 EP 9503980 W EP9503980 W EP 9503980W WO 9611901 A1 WO9611901 A1 WO 9611901A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl radical
group
phenyl
hydrogen
benzyl
Prior art date
Application number
PCT/EP1995/003980
Other languages
German (de)
English (en)
Inventor
Edgar Voss
Johannes Pill
Peter Freund
Original Assignee
Boehringer Mannheim Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to AU38406/95A priority Critical patent/AU3840695A/en
Publication of WO1996011901A1 publication Critical patent/WO1996011901A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings

Definitions

  • the present invention relates to ⁇ , ⁇ , ⁇ ', ⁇ '-tetrachlorodicarboxylic acids, processes for their preparation and medicaments which contain these compounds.
  • the invention relates to ⁇ . ⁇ ⁇ '. ⁇ '-tetrachlorodicarboxylic acids of the general formula I.
  • a and A ' are a straight-chain or branched alkylene chain with 1-10 carbon atoms
  • R- * can be hydrogen, benzyl, phenyl or a C 1 -C 4 -alkyl radical, a carbonyl, sulfoxide or sulfone group, an E or Z vinylene or an acetylene group, a CR2-R3 group, R2 is hydrogen, a C *
  • R3 is a C1-C4-alkyl radical, benzyl, phenyl, hydroxy or a group NR4R5,
  • R4 is hydrogen, benzyl, phenyl or a C 1 -C 4 -alkyl radical and
  • R5 is hydrogen or a C *
  • -C4-alkyl radical can be a group Y-W-Y,
  • W can be an alkylene chain (CH2) n and n 1-5 means
  • EP-A-0 279 978 already describes ⁇ , ⁇ , ⁇ ', ⁇ '-tetrachlorodicarboxylic acids which are suitable as medicaments for the treatment of obesity, hyperlipidemia or diabetes.
  • the compounds of the formula I show a strong inhibition of insulin-induced lipogenesis in vitro and are therefore suitable for the treatment of metabolic diseases.
  • the new compounds have a significantly greater inhibition of triglyceride synthesis with comparable inhibition of cholesterol synthesis.
  • Compounds of the formula I normalize elevated glucose levels without an accompanying risk of hypoglycaemia and are outstandingly suitable for the therapy of diabetes mellitus.
  • Diabetics often suffer from a general derailment of the entire metabolism, characterized by hyperlipidemia. Cholesterol elevation, hypertension, obesity and hyperinsulinemia. a clinical picture, which is referred to as metabolic syndrome or syndrome X and causes late complications of the greatest extent. In addition to the breakdown of hyperinsulinism, compounds of the general formula I also bring about a reduction in triglycerides, cholesterol and fibrinogen. They are therefore ideal for the treatment of the metabolic syndrome.
  • Preferred compounds of the general formula I are compounds in which A and A 'are a straight-chain alkylene chain having 2-5 C atoms and B is a phenylene, acetylene or (Z) or (E) -vinylene group, an oxygen atom, a sulfur atom , an SO or S ⁇ 2 group, an S- (CH2) 3 ⁇ S group or a -CH (phenyl) group.
  • Particularly preferred compounds of the general formula I are compounds in which A and A 'is a straight-chain alkylene chain of 5 methylene groups and B is an acetylene or (Z) - or (E) -vinylene group.
  • physiologically usable salts of the compounds of the formula I are alkali metal, alkaline earth metal, ammonium and alkylammonium salts, such as the Na, K, Ca or tetramethylammonium salt.
  • esters of compounds of the formula I are alkyl esters with 1 to 5 carbon atoms.
  • In vivo hydrolyzable derivatives of the compounds of formula I are e.g. B. salts with pharmacologically acceptable alkali, alkaline earth or ammonium bases; Esters, especially lower alkyl esters with 1 - 6 carbon atoms. such as B. methyl, ethyl and isopropyl esters; Amides, the nitrogen atom of which may optionally be mono- or disubstituted by alkyl groups having 1-6 carbon atoms, such as. B. N-methylamide and N, N-dimethylamide.
  • the dicarboxylic acid derivatives of the general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium
  • Such additives are e.g. B. tartrate or borate buffer, ethanol, dimethyl sulfoxide, complexing agents (such as ethylene diamine tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control or polyethylene derivatives of
  • Solid carriers are e.g. B. starch, lactose, mannitol, methyl cellulose, talc, finely divided silica, higher molecular weight polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the dose administered depends on the age, the health and the weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 50 mg / kg body weight. Normally 0.5 to 40 and preferably 1.0 to 20 mg / kgday are effective in one or more applications per day in order to obtain the desired results.
  • X - -ABA 1 - X (II) with dichloroacetic acid or esters of dichloroacetic acid in the presence of strong bases.
  • the reaction is usually carried out in solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, diethylene glycol dimethyl ether or t-butyldimethyl ether at temperatures between -80 ° C. and -20 ° C.
  • Preferred base is lithium diisopropylamide (LDA).
  • LDA lithium diisopropylamide
  • the products are usually purified by flash chromatography on silica gel and / or recrystallization of the sodium salts from alcohols such as methanol, ethanol or isopropanol.
  • the starting compounds of the formula II are known from the literature or can be prepared by processes known per se.
  • Example 2 Analogously to Example 1 from 5,5'-dibromodipentyl ether 18 and dichloroacetic acid, mobile phase. Ethyl acetate / heptane 1: 2, yield 32% colorless oil. An analytical sample was dissolved in ethanol and converted into the disodium salt with the calculated amount of solid sodium hydrogen carbonate. After removal of the solvent, the mixture was crystallized using ethyl acetate and isohexane. Colorless crystals, mp 61-62 ° C with decomposition.
  • Rat hepatocytes in culture are suitable for studies of cellular metabolism. These P ⁇ mark cultures offer the advantage that several substances can be examined in a comparative manner in a nonproliferative system, ie, p ⁇ mar, determined by Metaboh processes
  • Rat hepatocytes were isolated by recirculating collagenase perfusion and cultured in slanting tubes.
  • the 14 C-acetate assembly in T ⁇ glycende (TG) and Cholestenn (CH) was examined in the presence and absence of test substances.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés de la formule (I), dans laquelle A et A' désignent, indépendamment l'un de l'autre, une chaîne alkylène linéaire ou ramifiée ayant entre 1 et 10 atomes de carbone, B désigne ortho, méta ou para-phénylène, 1,2, 1,3 ou 1,4-cyclohexylidène, soufre, oxygène ou NR1, où R1 peut être hydrogène, benzyle, phényle ou un reste alkyle C1-C4, un groupe carbonyle, oxyde sulfonique ou sulfone, un groupe E ou Z-vinylène ou un groupe acétylène, un groupe CR2-R3-, R2 désigne hydrogène, un reste alkyle C1-C4 ou phényle, R3 désigne un reste alkyle C1-C4, benzyle, phényle, hydroxy ou un groupe NR4R5, R4 désigne hydrogène, benzyle, phényle ou un reste alkyle C1-C4, et R5 peut être hydrogène ou un reste alkyle C1-C4, un groupe Y-W-Y, Y désigne soufre ou oxygène, W désigne une chaîne alkylène (CH2)n et n vaut entre 1 et 5. L'invention concerne en outre leurs isomères optiques ainsi que leurs sels et leurs esters physiologiquement compatibles. L'invention concerne également leur procédé de préparation et des médicaments contenant ces composés et servant à traiter le syndrome métabolique.
PCT/EP1995/003980 1994-10-13 1995-10-10 NOUVEAUX ACIDES α,α,α',α'-TETRACHLORODICARBOXYLIQUES, LEUR PROCEDE DE PREPARATION ET MEDICAMENTS LES CONTENANT WO1996011901A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38406/95A AU3840695A (en) 1994-10-13 1995-10-10 Novel alpha,alpha,alpha',alpha'-tetrachlorobicarboxylic acids, process for producing them and medicaments containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4436578.0 1994-10-13
DE19944436578 DE4436578A1 (de) 1994-10-13 1994-10-13 Neue alpha,alpha,alpha',alpha'-Tetrachlordicarbonsäuren, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel

Publications (1)

Publication Number Publication Date
WO1996011901A1 true WO1996011901A1 (fr) 1996-04-25

Family

ID=6530663

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/003980 WO1996011901A1 (fr) 1994-10-13 1995-10-10 NOUVEAUX ACIDES α,α,α',α'-TETRACHLORODICARBOXYLIQUES, LEUR PROCEDE DE PREPARATION ET MEDICAMENTS LES CONTENANT

Country Status (3)

Country Link
AU (1) AU3840695A (fr)
DE (1) DE4436578A1 (fr)
WO (1) WO1996011901A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017143946A1 (fr) * 2016-02-25 2017-08-31 中国科学院上海药物研究所 Composé d'acide gras, son procédé de préparation et son utilisation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2425674A1 (fr) 2000-10-11 2002-04-18 Jean-Louis H. Dasseux Composes et compositions de sulfure et de disulfure pour le traitement du cholesterol et utilisations associees
AU2003300439A1 (en) * 2003-12-24 2005-08-03 Esperion Therapeutics, Inc. Sulfide and disulfide compounds and compositions for cholesterol management and related uses

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2208398A1 (de) * 1972-02-23 1973-08-30 Dynamit Nobel Ag Verfahren zur herstellung von derivaten der 1,2-diphenyl-1,1,2,2-tetrachloraethan-4,4'-dicarbonsaeure

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2208398A1 (de) * 1972-02-23 1973-08-30 Dynamit Nobel Ag Verfahren zur herstellung von derivaten der 1,2-diphenyl-1,1,2,2-tetrachloraethan-4,4'-dicarbonsaeure

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017143946A1 (fr) * 2016-02-25 2017-08-31 中国科学院上海药物研究所 Composé d'acide gras, son procédé de préparation et son utilisation
US20190039989A1 (en) * 2016-02-25 2019-02-07 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Fatty acid compound, preparation method therefor and use therefor
US10414713B2 (en) 2016-02-25 2019-09-17 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Fatty acid compound, preparation method therefor and use therefor

Also Published As

Publication number Publication date
AU3840695A (en) 1996-05-06
DE4436578A1 (de) 1996-04-18

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